title: Allosteric LFA-1 inhibitors modulate natural killer cell function.
abstract: Natural killer (NK) cells are believed to play an important role in a variety of disease pathologies, including transplant rejection and autoimmunity. None of the therapeutic modalities currently available are known to potently interfere with NK cell activity. Here we demonstrate for the first time that low molecular weight inhibitors of the integrin lymphocyte function-associated antigen-1 (LFA-1) readily block NK cell adhesion, activation, and NK cell-mediated cytolysis in vitro, in contrast to other immunosuppressive agents. These effects were independent of the type of allosteric mechanism by which LFA-1 inhibition was achieved. In addition, we describe a simple, nonradioactive whole-blood assay that should be suitable to monitor NK cell activation in clinical practice. Taken together, our study underlines the importance of LFA-1 in NK cell effector functions and indicates that allosteric LFA-1 inhibitors may become important tools to further elucidate the therapeutic potential of NK cell modulation in immunological diseases.
authors.affiliation: Department of Autoimmunity, Novartis Institutes for BioMedical Research, Basel, Switzerland. gabriele.weitz@novartis.com
authors.forename: Gabriele
authors.initials: G
authors.lastname: Weitz-Schmidt
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chreng
authors.forename: Simone
authors.initials: S
authors.lastname: Riek
mesh_terms: D055592:Biophysical Phenomena; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1